Of the million elective open-heart surgeries performed globally each year, 1 to 3% of patients will die in the recovery room, 10% will leave the hospital with left ventricular dysfunction, up to 30% will experience atrial arrhythmias, and 24% of high risk patients will die within 3 years. Moreover, recent prospective studies have shown that patients with a slightly elevated post-operative creatine kinase (CK-MB) levels in their blood have significantly higher risk of early (first year) and late (3 to 5 years) morbidity and mortality. Perioperative and post-operative mortality and morbidity are related to iatrogenic ischemia-reperfusion injury during cardiac surgery, and to inadequate myocardial protection. In addition, in paediatric cardiac surgery more than 50% of infants have perioperative myocardial damage with a low cardiac output. For over two decades, a significant part of the iatrogenic injury has been linked to the type, composition and delivery of cardioplegia.
In 2000, about 64% of open-heart surgery operations performed were coronary artery bypass graft procedures, 24% were heart valve replacement or repair procedures, and about 12% were related to the repair of congenital heart defects. About 1.2% were neonatal/paediatric. The majority of open heart surgery operations (over 80%) require cardiopulmonary bypass and elective heart arrest using either a blood or crystalloid cardioplegia solution. During these procedures the heart may be arrested for 3 hours, but sometimes up to 4 to 6 hours. The amount of damage to the heart caused by 3-4 hours is such that the heart is increasingly less likely to recover function, and more likely than not recover after 4 hours arrest.
Cardioplegic compositions have been used to arrest or quieten the heart during surgery. Cardioplegic drugs are usually partially diluted and mixed with a carrier (e.g. ratio 4 blood:1 crystalloid), or used as a crystalloid alone. A small proportion of procedures are performed under what is called “miniplegia” or “microplegia” in which small amounts of the cardioplegic solution/drugs are mixed with large volumes of blood (e.g. ratio 66 blood:1 crystalloid). Miniplegia is delivered directly to the tissue of interest (eg the heart) rather than the larger amounts required to be delivered systemically. The objective has been to arrest the heart and create a “motionless, bloodless field” for the surgeon to operate and minimise damage to the tissue during the procedure (including the potentially substantial damage which can occur during reperfusion when the cardioplegia is removed and the heart reanimates). Dr. Melrose, in 1955, utilized the patient's own blood as the vehicle to administer potassium citrate into the aorta to arrest a heart. In 1976, Dr. Hearse described administering crystalloid cardioplegia. A few years later Buckberg and colleagues suggested using a patient's own blood as the major carrier because blood has an oxygen-carrying capacity, superior oncotic and buffering properties, and endogenous antioxidants. Whole blood cardioplegia has also been modified using larger volumes of blood and smaller titrations of potassium, hence the name “miniplegia”. The term “Miniplegia” was coined by Menasche and colleagues in the early 1990s. Miniplegia (or Microplegia) provided oxygen-rich blood coupled with micro titrations of arrest and additives to achieve a quiescence of the heart and reduce ischemia-reperfusion injury.
Ischemic injury to a large extent is dependent upon the duration of the ischemic event, whether global or regional in nature. With ischemia being defined as the mismatch between oxygen supply (coronary blood flow and oxygen carrying capacity) and oxygen demand (determined by the wall stress, heart rate and contractility or inotropic state of the heart), the severity of ischemia is an important factor determining subsequent injury. The severity of ischemia can be offset, and even neutralized, by increased collateral blood flow. The basic premise of “miniplegia” is to minimize ischemia and therefore injury.
By definition, maintenance of cardiac aerobic metabolism during arrest requires oxygen supply to match oxygen demand. Consequently, where the oxygen demand has been drastically reduced by over 90% during adequate cardioplegic induction and maintenance of asystole, for the heart to maintain aerobic metabolism a number of factors or modalities must be met. These modalities can be summarized as follows: (i) oxygen must be present in sufficient quantities to match demand, and there is now convincing evidence that hematocrit should be at least equal to 24%; (ii) oxygen must be delivered at a sufficient flow rate to match demand; (iii) oxygen should be delivered in as near a continuous fashion as possible, without restricting surgeon's view, because it is consumed over time (no matter what the “safe” ischemic interval is in experimental models, it is virtually impossible to predict, in a given patient, the time point beyond which myocardial metabolism is going to shift from aerobic to anaerobic patterns as well as the extent and reversibility of tissue damage that may occur beyond this cut-off time mark); and (iv) oxygen must be delivered as uniformly as possible throughout the myocardium. When tight stenosis and furthermore, complete occlusions of the coronary arteries are present, there is now a convincing body of evidence that retrograde or, even better, a combined retrograde/antegrade approach are more effective in ensuring homogeneous distribution of cardioplegia than the antegrade route administration alone.
While early reperfusion, or restoration of the blood flow, remains the most effective means of salvaging the myocardium from acute ischaemia, the sudden influx of oxygen paradoxically may lead to necrosis, arrhythmias and death. The extent of “reperfusion injury” has been linked to a cascade of inflammatory reactions including the generation of cytokines, leukocytes, reactive oxygen species and free radicals. Reperfusion of ischaemic myocardium is necessary to salvage tissue from eventual death. However, reperfusion after even brief periods of ischaemia is associated with pathologic changes that represent either an acceleration of processes initiated during ischaemia per se, or new pathophysiological changes that were initiated after reperfusion. The degree and extent of reperfusion injury can be influenced by inflammatory responses in the myocardium. Ischaemia-reperfusion prompts a release of oxygen free radicals, cytokines and other pro-inflammatory mediators that activate both the neutrophils and the coronary vascular endothelium. The inflammatory process can lead to endothelial dysfunction, microvascular collapse and blood flow defects, myocardial infarction and apoptosis. Pharmacologic anti-inflammatory therapies targeting specific steps have been shown to decrease infarct size and myocardial injury.
Hypothermia has been an essential component of myocardial protection since the very beginning. The focus has always been on reducing metabolism to the lowest possible level during ischemic interval so that myocardial energy stores (adenosine tri-phosphate and glycogen) are maintained and tissue acidosis is avoided during this ischemic episode. However, many investigators have found that the level of myocardial recovery after crystalloid cardioplegia utilizing 10° C. or 25° C. was not significantly different. Until recently the major focus of myocardial protection has been that of preserving myocyte contractility to prevent pump failure which includes conserving cell energy by reducing metabolism to a low level which allows continued support of vital cell activities such as ion pumping to maintain internal milieu. Not only is there much interest in the current techniques involving cardiac and systemic temperature during cardioplegia, but also in the effect of cardioplegia on the endothelium and microvascular compartments. Thus, endothelium preservation may be as important as myocyte preservation.
Current techniques still result in a substantial number of patients suffering atrial fibrillation post-operatively. Patients typically require several days in intensive care following the operation, and take some time to return to lucidity and mobility. These reflect the damage, some of which is reversible, that results from current procedures and the need for improved techniques.